Oxidative damage to the ocular lens has been recognized as a primary event in the pathogonesis of many forms of cataract. [Augusteyn, R. C. (1981), Protein modification in cataract: Possible oxidative mechanisms. In "Mechanisms of cataract formation in the human lens", (Ed. Duncan, G.) Pp.71-115. Academic Press, Inc., N.Y.] This oxidative damage can be caused by various reactive oxygen species, including H.sub.2 O.sub.2 and the oxygen free radicals O.sub.2.sup..- and HO.sup.., which are generated in the lens through reduction of molecular oxygen. [Bhuyan and Bhuyan, Current Eye Research, 3(1), 67-81 (1984)]. For example, it has been shown that H.sub.2 O.sub.2 is present in the human eye and is increased in concentration in cataracts. [Bhuyan et al., I.R.C.S. Med. Sci. 9, 126-27 (1981); Spector and Garner, Exp. Eye Res. 33, 673-81 (1981)].
Oxidative damage can occur through oxidation of crucial sulfhydryl groups of cysteine and methionine amino acids of enzymes and/or membrane proteins. This oxidation can result in inactivation of enzymes and cross-linking of lenticular proteins resulting in the formation of insoluble aggregates of protein which reduce the transparent nature of the lens. For example, senile nuclear cataract formation has been found to be accompanied by a progressive oxidation of cysteine and methionine. [Truscott and Augusteyn, Biochim. et Biophys. Acta 492, 43-52 (1977)]. Oxidative damage can also occur through peroxidation of lenticular plasma membrane lipids. It has been shown that there is enhanced lipid peroxidation in human senile cataract. [Bhuyan et al., I.R.C.S. Med. Sci. 9, 126-27 (1981); Bhuyan et al., Invest. Ophthalmol. Vis. Sci.(Supp.) 18, 97 (Abstr. 4) (1979)]. Peroxidation of plasma membrane lipid can disrupt the physico-chemical properties of the plasma membrane which results in an altered membrane physical characteristics and altered transport function of the membrane.
In the eye, there are two types of natural defenses against the oxidative damage caused by reactive oxygen species, i.e., an enzymatic defense and a nonenzymatic defense. The enzymmatic defense provides protective ocular enzymes, such as superoxide dismutase (O.sub.2.sup..- :O.sub.2.sup..- oxidoreductase), catalase (H.sub.2 O.sub.2 :H.sub.2 O.sub.2 oxidoreductase) and gluthathione peroxidase (GSH:H.sub.2 O.sub.2 oxidoreductase), which act to reduce the concentrations of reactive oxygen species. These enzymes convert the reactive oxygen species to harmless species, such as water or oxygen, before they can cause oxidative damage to lenticular lipid or protein.
It has been shown that in human senile cataract, cortical activities of the three protective ocular enzymes were markedly decreased. [Bhuyan et al., I.R.C.S. Med. Sci. 9, 126-27 (1981)]. It has further been shown that catalase is inhibited by O.sub.2.sup..- and that his inhibition can be prevented and reversed by superoxide dismutase. [Kono and Fridovich, J. Biol. Chem. 257, 5751 (1982)]. Catalase and superoxide dismutase act synergistically in that superoxide dismutase removes the reactive oxygen species O.sub.2.sup..- thus reducing the concentration of a catalase inhibitor and allowing catalase to operate at a higher activity in removing H.sub.2 O.sub.2.
The nonenzymatic defense against the oxidative damage caused by reactive oxygen species involves the action of naturally occurring antioxidants such as glutathione (GSH), ascorbic acid (vitamin C), .alpha.-tocopherol (vitamin E) and other biological antioxidants. These naturally occurring agents function by inhibiting the formation of the reactive oxygen species. [Reddan et al., Exp. Eye Res. 45, 209-21 (1988)] In particular, in vitro and in vivo studies in different animal species have demonstrated a significant protective effect of vitamins C and E against light, sugar and steroid induced cataracts. [Gerster, Z. Ernahrungswiss 28, 56-75 (1989)].
A number of forms of cataracts exist in man including senile cataracts, which develop in the aged, sugar-induced cataracts, which develop coincidentally with high concentrations of blood sugars such as in galactosemia, and steroid-induced cataracts, which develop due to elevated steroid levels. Guinea pigs fed a high concentration of galactose have been shown to develop cataracts. Kosegarten and Maher [J. Pharm. Sci. 67, 1478-79 (1978)] have proposed the galactose-fed guinea pig as a model for galactose-induced cataract formation in man.
It has now been found that certain bis(alkyl-substituted-4-hydroxyphenylthio)alkane analogs inhibit the formation of cataracts. These bis(alkyl-substituted-4-hydroxyphenylthio)alkane analogs which are useful in the method of use of the present invention are compounds of the type disclosed in U.S. Pat. Nos. 3,576,883, 3,786,100, 3,862,332, 3,897,500 and 4,900,757. These compounds include 2,2'-bis(3,5-di-tertiarybutyl-4-hydroxy phenylthio)propane, also known generically as probucol. Probucol is an agent used to reduce total serum cholesterol in man. It has been reported that probucol inhibits oxidative modification of low density lipoprotein [Parthasarathy et al., J. Clin. Invest. 77, 641-43 (1986); Carew et al., Proc. Natl. Acad. Sci. USA 84, 7725-29 (1987)] and that the antioxidant activity of probucol reduces atherosclerosis in Watanabe rabbits [Mao et al., International Atherosclerosis Congress, 53rd Annual Meeting of the European Atherosclerosis Society, Apr. 20-22, 1989, Vienna].